The primary cellular defense system against protein misfolding and impaired clearance is the functional network of chaperone proteins, such as TRiC, which are both responsible for the proper folding of normal proteins and the attempt to refold or initiate destruction of damaged and genetically abnormal proteins. Compelling evidence from model systems supports the view that the proteostasis network can be modulated to improve the outcome of the cellular challenges presented by the toxic protein species responsible for neurodegenerative disease. However, to date, no effective therapeutic intervention for any neurodegenerative disease has been developed based on any principle including modulation of the chaperone network. This proposal is focused on carrying out an integrated program of investigation whose goal is to create a strong framework in which basic science understanding of the structure of toxic species and their interaction with the proteostasis network is linked to translational approaches to reduce the accumulation of these species through reduced production and/or enhanced clearance. In so doing, the application addresses the critical societal goal of intercepting the oncoming epidemic of neurodegenerative disorders. We have chosen the paradigmatic neurodegenerative disease Huntington's disease and the TRiC chaperonin network as the focus of our program, based on strong data by our team that TRiC complex components provide clear beneficial effects on mutant HTT-induced phenotypes in model systems. In this Program Project we propose 3 integrated Projects and 2 supporting Cores to investigate mHTT-TRiC chaperonin interactions and determine how select TRiC related components contribute to or reduce mHTT-driven pathogenesis. The hypothesis that guides the proposal is that TRiC plays a critical role in regulating the accumulation of toxic form of the expanded repeat HTT protein and hence increasing the activity of TRiC and TRiC-derived proteins will abrogate and/or reverse mHTT-linked pathogenesis. We propose the following four overall Specific Aims: Aim 1: To characterize the interactions between TRiC reagents and aberrant forms of mHTT under in vitro and ex vivo conditions as well as in HD model cells and neurons. Aim 2: To investigate the impact of existing and novel TRiC reagents on the production and accumulation of mHTT species and cellular proteostasis. Aim 3: To systematically evaluate the impact of TRiC reagents on neuronal function and survival in cell culture. Aim 4: To systematically evaluate and compare the impact of TRiC reagent therapy in mouse models of HD through quantitative measures of neuronal structure, function and pathology. Our program will provide a framework for the extension of the study of TRiC based therapeutic strategies for other neurodegenerative disorders, including AD, PD, ALS or FTD. While our proposal will focus on TRiC-based therapeutics, our assays may point to the participation of chaperones that partner with TRiC in regulating mHTT effects and open the possibility of additional novel approaches to HD and related disorders.